Allostery in Drug Discovery
Published September 25, 2025 | Version v1
Journal article Open

MRAP2 modifies the signaling and oligomerization state of the melanocortin-4 receptor

Authors/Creators

  • 1. Max-Delbrück-Center for Molecular Medicine-Berlin, Berlin, Germany
  • 2. Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute for Experimental Paediatric Endocrinology, Berlin, Germany
  • 3. Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, UK
  • 4. Institute for Research in Immunology and Cancer, Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, QC, Canada
  • 5. Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Medical Physics and Biophysics, Group Structural Biology of Cellular Signaling, Berlin, Germany
  • 6. Centre for Endocrinology, William Harvey Research Institute Queen Mary University of London, London, UK
  • 7. School of Physics and Astronomy, University of St Andrews, St Andrews, UK
  • 8. School of Medicine, University of St Andrews, St Andrews, UK
  • 9. Faculty of Life Sciences, Institute of Biochemistry, University of Leipzig, Leipzig, Germany
  • 10. ISAR Bioscience Institute, Planegg/Munich, Germany
  • 11. Rudolf Boehm Institute for Pharmacology and Toxicology, University of Leipzig, Leipzig, Germany
  • 12. ROR icon "Dunarea de Jos" University of Galati

Description

The melanocortin-4 receptor is a G protein-coupled receptor and a key regulator of appetite and metabolism. It can interact with the melanocortin-receptor accessory protein 2, a single transmembrane helix protein known to interact with several different G protein-coupled receptors. However, the consequences of this interaction are not completely understood. Here we report that co-expression of melanocortin-receptor accessory protein 2 has multiple effects on the melanocortin-4 receptor: it enhances G protein-mediated signaling and simultaneously impairs β-arrestin2 recruitment and, consequently, internalization. In addition, co-expression of melanocortin-receptor accessory protein 2 leads to an increased number of monomers of melanocortin-4 receptor by disrupting receptor oligomers. A structural homology model of the active state melanocortin-4 receptor – melanocortin-receptor accessory protein 2 – Gαs complex suggests interaction sites that are relevant for receptor activation. Our data indicate that melanocortin-receptor accessory protein 2 is an accessory protein that interacts with and influences melanocortin-4 receptor structure, biasing its signaling towards G protein-mediated effects.

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